EP3436460A1 - Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf - Google Patents

Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf

Info

Publication number
EP3436460A1
EP3436460A1 EP17714785.7A EP17714785A EP3436460A1 EP 3436460 A1 EP3436460 A1 EP 3436460A1 EP 17714785 A EP17714785 A EP 17714785A EP 3436460 A1 EP3436460 A1 EP 3436460A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
heteroaryl
compound
formula
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP17714785.7A
Other languages
German (de)
English (en)
Other versions
EP3436460B1 (fr
Inventor
Michaël Louis Robert DELIGNY
Jag Paul Heer
Jean KEYAERTS
Luce Elsa LÉPISSIER
Martin Alexander Lowe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UCB Biopharma SRL
Sanofi SA
Original Assignee
UCB Biopharma SRL
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by UCB Biopharma SRL, Sanofi SA filed Critical UCB Biopharma SRL
Publication of EP3436460A1 publication Critical patent/EP3436460A1/fr
Application granted granted Critical
Publication of EP3436460B1 publication Critical patent/EP3436460B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems

Definitions

  • the present invention relates to a class of fused pentacyclic imidazole derivatives, and to their use in therapy. More particularly, this invention is concerned with
  • pharmacologically active substituted fused pentacyclic benzimidazole derivatives and analogues thereof are modulators of the signalling of TNFa, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.
  • TNFa is the prototypical member of the Tumour Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death.
  • TNF Tumour Necrosis Factor
  • One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors.
  • TNFa exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.
  • TNFa inhibitors include anti-TNFa antibodies; and soluble TNFa receptor fusion proteins.
  • anti-TNFa antibodies include fully human antibodies such as adalimumab (Humira®) and golimumab
  • chimeric antibodies such as infliximab (Remicade®), and pegylated Fab' fragments such as certolizumab pegol (Cimzia®).
  • An example of a commercially available soluble TNFa receptor fusion protein is etanercept (Enbrel®).
  • TNF superfamily members including TNFa itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M.G. Tansey & D.E. Szymkowski, Drug Discovery Today, 2009, 14, 1082-1088; and F.S. Carneiro et al., J. sexual Medicine, 2010, 7, 3823-3834).
  • the compounds in accordance with the present invention being potent modulators of human TNFa activity, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders;
  • cardiovascular disorders cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
  • certain compounds of this invention may be useful for coupling to a fluorophore to provide fluorescent conjugates that can be utilised in assays (e.g. a fluorescence polarisation assay) for detecting pharmacologically active compounds.
  • WO 2013/186229, WO 2014/009295 and WO 2014/009296 relate to fused bicyclic imidazole derivatives which are modulators of the signalling of TNFa.
  • WO 2015/086525 and WO 2015/086526 relate to fused tricyclic imidazole derivatives which are modulators of the signalling of TNFa.
  • Co-pending international patent application PCT/EP2015/072868 (published on 7 April 2016 as WO 2016/050975) relates to fused pentacyclic imidazole derivatives which are modulators of the signalling of TNFa.
  • the present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
  • A represents N or C-R 6 ;
  • B represents N or C-R 7 ;
  • D represents N or C-R 8 ;
  • E represents a fused heteroaromatic ring system selected from the groups of form la (Ea), (Eb) and (Ec):
  • R 1 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -S0 2 R a , -NR b R c , -NR c COR d , -NR c C0 2 R d , -NHCONR b R c , -NR c S0 2 R e , -COR d , -C0 2 R d , -CONR b R c , -S0 2 NR b R c , or -S(0)(N-R b )R e ; or R 1 represents Ci_ 6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, aryl, aryl(Ci- 6 )alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, hetero
  • R 2 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or -OR a ; or R 2 represents Ci- 6 alkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
  • R 3 and R 4 independently represent hydrogen, halogen or trifluoromethyl; or C 1-6 alkyl, which group may be optionally substituted by one or more substituents; - -
  • R 5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoro- methoxy, trifluoromethoxy, -OR a or Ci- 6 alkylsulphonyl; or R 5 represents Ci- 6 alkyl, which group may be optionally substituted by one or more substituents;
  • R 6 , R 7 and R 8 independently represent hydrogen, halogen, trifluoromethyl, Ci- 6 alkyl or Ci- 6 alkoxy;
  • R 12 represents hydrogen or Ci- 6 alkyl
  • R a represents Ci- 6 alkyl, C3-7 cycloalkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R b and R c independently represent hydrogen or trifluoromethyl; or C 1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R b and R c when taken together with the nitrogen atom to which they are both attached, represent a heterocyclic moiety selected from azetidin- 1 -yl, pyrrolidin- 1 -yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin- 4-yl, homopiperazin-l-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl and (dioxo)- thiazinan-4-yl, any of which groups may be optionally substituted by one or more substituents;
  • R d represents hydrogen; or R d represents Ci- 6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • R e represents Ci- 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • R f and R g independently represent hydrogen or Ci- 6 alkyl.
  • the present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated. - -
  • the present invention provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a
  • cardiovascular disorder a metabolic disorder, an ocular disorder, or an oncological disorder.
  • the present invention also provides the use of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated.
  • the present invention provides the use of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of an
  • inflammatory or autoimmune disorder a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
  • the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a
  • the present invention provides a method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. - -
  • the present invention includes within its scope salts of the compounds of formula (I) above.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts:
  • the present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents or water.
  • the present invention also includes within its scope co-crystals of the compounds of formula (I) above.
  • co-crystal is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio.
  • the preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).
  • Suitable alkyl groups which may be present on the compounds in accordance with the invention include straight-chained and branched C 1-6 alkyl groups, for example alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Suitable alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- vXy ⁇ , 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as "Ci- 6 alkoxy", “Ci- 6 alkylthio", "Ci- 6 alkylsulphonyl" and "Ci- 6 alkylamino" are to be construed accordingly.
  • C3-7 cycloalkyl refers to monovalent groups of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo- fused analogues thereof. Suitable C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
  • C4-7 cycloalkenyl refers to monovalent groups of 4 to 7 carbon atoms derived from a partially unsaturated monocyclic hydrocarbon. Suitable C4-7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. - -
  • C4-9 bicycloalkyl refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.
  • aryl refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci_6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • C3-7 heterocycloalkyl refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo- furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, dioxanyl, tetrahydrothiopyranyl, piperidinyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydro- isoquinolinyl, piperazinyl, 1 ,2,3,4-tetrahydroquinoxalinyl, hexahydro-[l,2,5]thiadiazolo- [2,3-a]pyrazinyl, homopiperazinyl,
  • C3-7 heterocycloalkenyl refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl and 1 ,2,3,6-tetrahydropyridinyl.
  • C4-9 heterobicycloalkyl corresponds to C4-9 bicycloalkyl wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Typical heterobicycloalkyl groups include 3- azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.
  • C4-9 spiroheterocycloalkyl refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom.
  • Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]- heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]- octanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro- [3.5]nonanyl and 2,4,8-triazaspiro[4.5]decanyl.
  • heteroaryl refers to monovalent aromatic groups containing at least 5 atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-£][l,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-£]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-£]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimid
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
  • Formula (I) and the formulae depicted hereinafter are intended to - - -
  • 2-oxo-(lH)-pyridinyl is a tautomer of 2-hydroxypyridinyl
  • 2-oxo-(lH)-pyrimidinyl is a tautomer of 2-hydroxypyrimidinyl
  • each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 3 ⁇ 4 2 H (deuterium) or 3 H (tritium) atom, preferably 3 ⁇ 4
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • a particular sub-class of compounds in accordance with the present invention is represented by formula (IA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
  • A represents N. In a second embodiment, A represents C-R 6 .
  • B represents N. In a second embodiment, B represents
  • D represents N. In a second embodiment, D represents
  • A, B and D all represent N.
  • a and B both represent N, and D represents C-R 8 .
  • a and D both represent N, and B represents C-R 7 .
  • A represents N, B - -
  • A represents C-R 7 , and D represents C-R 8 .
  • A represents C-R 6 , and B and D both represent N.
  • A represents C-R 6 , B represents N, and D represents C-R 8 .
  • A represents C-R 6 , B represents C-R 7 , and D represents N.
  • A represents C-R 6 , B represents C-R 7 , and D represents C-R 8 .
  • At least one of A, B and D is other than N.
  • E represents a fused heteroaromatic ring system of formula (Ea) or
  • E represents a fused heteroaromatic ring system of formula (Ea).
  • E represents a fused heteroaromatic ring system of formula (Eb).
  • E represents a fused heteroaromatic ring system of formula
  • Particular sub-classes of compounds in accordance with the present invention include the compounds of formula (IB), (IC) and (ID) and N-oxides thereof, and pharmaceutically acceptable salts thereof:
  • Particular sub-classes of compounds in accordance with the present invention include the compounds of formula (IB) and (IC) as defined above.
  • R 1 represents hydrogen, halogen or cyano; or R 1 represents aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, heteroaryl-aryl-, (C3-7)cycloalkyl- heteroaryl-, (C4-9)bicycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C4-9)- heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen; or R 1 represents C3-7 heterocycloalkyl, heteroaryl, (C3-7)cycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl- or (C4-9)- heterobicycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen; or R 1 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 1 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 1 represents hydrogen
  • R 1 represents halogen. In one aspect of that
  • R 1 represents fluoro. In another aspect of that embodiment, R 1 represents chloro.
  • R 1 represents cyano
  • R 1 represents optionally substituted aryl. In one aspect of that embodiment, R 1 represents optionally substituted phenyl.
  • R 1 represents optionally substituted C3-7 heterocycloalkyl. In one aspect of that embodiment, R 1 represents optionally substituted azetidinyl.
  • R 1 represents optionally substituted (C3-7)hetero- cycloalkenyl.
  • R 1 represents optionally substituted 1 ,2-dihydropyridinyl.
  • R 1 represents optionally substituted 1 ,2-dihydropyrimidinyl. - -
  • R 1 represents optionally substituted heteroaryl. In one aspect of that embodiment, R 1 represents optionally substituted pyridinyl. In another aspect of that embodiment, R 1 represents optionally substituted pyrimidinyl.
  • R 1 represents optionally substituted heteroaryl-aryl-. In one aspect of that embodiment, R 1 represents optionally substituted imidazolylphenyl-.
  • R 1 represents optionally substituted (C3-7)cycloalkyl- heteroaryl-.
  • R 1 represents optionally substituted cyclohexylpyrazolyl-.
  • R 1 represents optionally substituted cyclopropylpyridinyl-.
  • R 1 represents optionally substituted cyclobutylpyridinyl-.
  • R 1 represents optionally substituted cyclopentylpyridinyl-.
  • R 1 represents optionally substituted cyclohexylpyridinyl-.
  • R 1 represents optionally substituted cyclopropylpyrimidinyl-. In a seventh aspect of that embodiment, R 1 represents optionally substituted cyclobutyl- pyrimidinyl-. In an eighth aspect of that embodiment, R 1 represents optionally substituted cyclopentylpyrimidinyl-. In a ninth aspect of that embodiment, R 1 represents optionally substituted cyclohexylpyrimidinyl-. In a tenth aspect of that embodiment, R 1 represents optionally substituted cyclohexylpyrazinyl-.
  • R 1 represents optionally substituted (C4-s>)bicycloalkyl- heteroaryl-.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl- heteroaryl-.
  • R 1 represents substituted azetidinylpyrazolyl-.
  • R 1 represents optionally substituted pyrrolidinylpyridinyl-.
  • R 1 represents optionally substituted tetrahydropyranylpyridinyl-.
  • R 1 represents optionally substituted piperidinylpyridinyl-.
  • R 1 represents optionally substituted piperazinylpyridinyl-.
  • R 1 represents optionally substituted morpholinylpyridinyl-.
  • R 1 represents optionally substituted
  • R 1 represents optionally substituted diazepanylpyridinyl-. In a ninth aspect of that embodiment, R 1 represents optionally substituted oxetanylpyrimidinyl-. In a tenth aspect of that embodiment, R 1 represents optionally substituted azetidinylpyrimidinyl-. In an eleventh - -
  • R 1 represents optionally substituted tetrahydrofuranyl- pyrimidinyl-. In a twelfth aspect of that embodiment, R 1 represents substituted tetrahydrothienyl-pyrimidinyl-. In a thirteenth aspect of that embodiment, R 1 represents optionally substituted pyrrolidinylpyrimidinyl-. In a fourteenth aspect of that
  • R 1 represents optionally substituted tetrahydropyranylpyrimidinyl-. In a fifteenth aspect of that embodiment, R 1 represents optionally substituted dioxanyl- pyrimidinyl-. In a sixteenth aspect of that embodiment, R 1 represents optionally substituted piperidinylpyrimidinyl-. In a seventeenth aspect of that embodiment, R 1 represents optionally substituted piperazinylpyrimidinyl-. In an eighteenth aspect of that embodiment, R 1 represents optionally substituted morpholinylpyrimidinyl-. In a nineteenth aspect of that embodiment, R 1 represents optionally substituted
  • R 1 represents optionally substituted azepanylpyrimidinyl-.
  • R 1 represents optionally substituted oxazepanylpyrimidinyl-.
  • R 1 represents optionally substituted diazepanylpyrimidinyl-.
  • R 1 represents optionally substituted
  • R 1 represents optionally substituted oxetanylpyrazinyl-. In a twenty-fifth aspect of that embodiment, R 1 represents optionally substituted piperidinylpyrazinyl-.
  • R 1 represents optionally substituted (C4-9)- heterobicycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted (2-oxa-5-azabicyclo[2.2.1]heptanyl)pyrimidinyl-.
  • R 1 represents optionally substituted (3-oxa-8-azabicyclo- [3.2. l]octanyl)pyrimidinyl-.
  • R 1 represents optionally substituted (3,6-diazabicyclo[3.2.2]nonanyl)pyrimidinyl-.
  • R 1 represents optionally substituted (3,7-dioxa-9-azabicyclo[3.3.1]- nonany l)pyrimidiny 1- .
  • R 1 represents optionally substituted (C4-9)spiro- heterocycloalkyl-heteroaryl- .
  • R 1 represents fluoro, chloro or cyano; or R 1 represents phenyl, azetidinyl, dihydropyridinyl, dihydropyrimidinyl, pyrazolyl, pyridinyl, pyrimidinyl, imidazolylphenyl, cyclopropylpyridinyl, cyclobutylpyridinyl, cyclobutylpyrimidinyl, cyclohexylpyrimidinyl, azetidinylpyrazolyl, oxetanylpyridinyl, azetidinylpyridinyl, - -
  • pyrrolidinylpyridinyl piperazinylpyridinyl, oxetanylpyrimidinyl, azetidinylpyrimidinyl, tetrahydrofuranylpyrimidinyl, tetrahydrothienylpyrimidinyl, pyrrolidinylpyrimidinyl, tetrahydropyranylpyrimidinyl, dioxanylpyrimidinyl, piperazinylpyrimidinyl, morpholinyl- pyrimidinyl, thiomorpholinylpyrimidinyl, diazepanylpyrimidinyl, (2-oxa-5-azabicyclo- [2.2.1]heptanyl)pyrimidinyl, (3-oxa-8-azabicyclo[3.2.1]octanyl)pyrimidinyl, (3,6- diazabicyclo[3.2.2]nonanyl)pyrimidinyl or (3,7-dio
  • R 1 represents fluoro or chloro; or R 1 represents pyrimidinyl, cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, oxetanylpyrimidinyl, tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl, tetrahydropyranylpyrimidinyl, dioxanylpyrimidinyl or morpholinylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents chloro; or R 1 represents pyrimidinyl, which group may be optionally substituted by one or more substituents.
  • R 1 represents pyrimidinyl, which group may be optionally
  • Typical examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, halo(Ci-6)alkyl, cyano, cyano(Ci-6)alkyl, nitro(Ci-6)alkyl, Ci- 6 alkyl, phosphate(Ci_6)alkyl, (Ci-6)alkylphosphate(Ci-6)alkyl, phosphate(Ci-6)alkoxy(Ci-6)alkyl, sulphate(Ci_6)alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, C2-6 alkenyl, hydroxy, hydroxy(Ci-6)alkyl, Ci- 6 alkoxy, (Ci-6)alkoxy(Ci-6)- alkyl, trifluoroethoxy, carboxy(C3-7)cycloalkyloxy, Ci- 6 alkylthio, Ci- 6 alkylsulphonyl, (Ci-6)al
  • optional substituents on R 1 include one, two or three substituents independently selected from halogen, cyano, Ci- 6 alkyl, difluoromethyl, hydroxy(Ci_6)alkyl, oxo, amino and amino(Ci-6)alkyl.
  • R 1 Particular examples of optional substituents on R 1 include one, two or three substituents independently selected from hydroxy(Ci_6)alkyl and amino(Ci-6)alkyl.
  • substituents on R 1 include one, two or three substituents independently selected from fluoro, chloro, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, cyano isopropyl, nitromethyl, methyl, ethyl, isopropyl, isopropylmethyl, phosphate-isopropyl, ethylphosphate-isopropyl, phosphate-methoxyisopropyl, sulphate- isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy,
  • substituents on R 1 include one, two or three substituents independently selected from fluoro, cyano, methyl, difluoromethyl, hydroxyisopropyl, oxo, amino and aminoisopropyl.
  • Suitable examples of particular substituents on R 1 include one, two or three substituents independently selected from hydroxyisopropyl and aminoisopropyl.
  • R 1 is substituted by hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R 1 is substituted by hydroxyisopropyl, especially 2-hydroxyprop-2-yl. - -
  • R 1 is substituted by amino(Ci-6)alkyl. In one aspect of that embodiment, R 1 is substituted by aminoisopropyl, especially 2-aminoprop-2-yl.
  • R 1 Illustrative values of R 1 include fluoro, chloro, cyano, (methyl)(methylthio)phenyl, methylsulphonylphenyl, (methyl)(methylsulphonyl)phenyl, methylsulphoximinylphenyl, (hydroxyisopropyl)azetidinyl, methylpyrazolyl, hydroxyisopropylpyridinyl,
  • R 1 Typical values of R 1 include fluoro, chloro, hydroxyisopropylpyrimidinyl, amino isopropylpyrimidinyl, aminocyclobutylpyrimidinyl, (amino)(cyano)cyclobutyl- pyrimidinyl, (amino)(difluoromethyl)cyclobutylpyrimidinyl, aminocyclopentyl- pyrimidinyl, (amino)(difluoro)cyclohexylpyrimidinyl, (amino)oxetanylpyrimidinyl, aminotetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpyrrolidinyl- pyrimidinyl, aminotetrahydropyranylpyrimidinyl, (amino)(dimethyl)dioxanylpyrimidinyl, (hydroxyisopropyl)piperidinylpyrimidinyl,
  • Selected values of R 1 include chloro, hydroxyisopropylpyrimidinyl and amino- isopropylpyrimidinyl.
  • R 1 represents hydroxyisopropylpyrimidinyl, especially 2-(2-hydroxypropan-2-yl)pyrimidin-5-yl.
  • R 1 represents aminoisopropylpyrimidinyl, especially 2-(2- aminopropan-2-yl)pyrimidin-5 -yl.
  • R 2 represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy or -OR a ; or R 2 represents Ci- 6 alkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
  • R 2 represents hydrogen or halogen; or R 2 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 2 represents halogen; or R 2 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 2 represents hydrogen or halogen.
  • R 2 represents hydrogen. In a second embodiment, R 2 represents halogen. In one aspect of that embodiment, R 2 represents fluoro. In another - -
  • R 2 represents chloro. In a third embodiment, R 2 represents cyano. In a fourth embodiment, R 2 represents nitro. In a fifth embodiment, R 2 represents hydroxy. In a sixth embodiment, R 2 represents trifluoromethyl. In a seventh embodiment,
  • R 2 represents trifluoromethoxy. In an eighth embodiment, R 2 represents -OR a . In a ninth embodiment, R 2 represents optionally substituted Ci- 6 alkyl. In a first aspect of that embodiment, R 2 represents methyl. In a second aspect of that embodiment, R 2 represents ethyl. In a tenth embodiment, R 2 represents optionally substituted heteroaryl. In a first aspect of that embodiment, R 2 represents optionally substituted pyrimidinyl.
  • Typical examples of optional substituents on R 2 include one, two or three substituents independently selected from hydroxy(Ci-6)alkyl and C2-6 alkoxycarbonyl.
  • Suitable examples of optional substituents on R 2 include one, two or three substituents independently selected from hydroxy(Ci-6)alkyl.
  • Typical examples of particular substituents on R 2 include one, two or three substituents independently selected from hydroxyisopropyl and ethoxycarbonyl.
  • Suitable examples of particular substituents on R 2 include one, two or three substituents independently selected from hydroxyisopropyl.
  • Typical values of R 2 include hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, -OR a , methyl, ethoxycarbonylethyl and hydroxyisopropylpyrimidmyl.
  • R 2 examples include hydrogen and fluoro.
  • R 3 represents hydrogen, halogen or C 1-6 alkyl.
  • R 3 represents hydrogen. In a second embodiment, R 3 represents halogen. In one aspect of that embodiment, R 3 represents fluoro. In a third embodiment, R 3 represents optionally substituted Ci- 6 alkyl. In one aspect of that embodiment, R 3 represents methyl. In another aspect of that embodiment, R 3 represents ethyl.
  • R 4 represents hydrogen, halogen or C 1-6 alkyl.
  • R 4 represents hydrogen. In a second embodiment, R 4 represents halogen. In one aspect of that embodiment, R 4 represents fluoro. In a third embodiment, R 4 represents optionally substituted Ci- 6 alkyl. In one aspect of that embodiment, R 4 represents methyl. In another aspect of that embodiment, R 4 represents ethyl. - -
  • R 5 represents halogen, cyano, difluoromethoxy, trifluoromethoxy, -OR or C 1-6 alkylsulphonyl; or R 5 represents Ci- 6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 5 represents difluoromethoxy or -OR a .
  • R 5 represents hydrogen. In a second embodiment, R 5 represents halogen. In one aspect of that embodiment, R 5 represents fluoro. In another aspect of that embodiment, R 5 represents chloro. In a third embodiment, R 5 represents hydroxy. In a fourth embodiment, R 5 represents cyano. In a fifth embodiment, R 5 represents trifluoromethyl. In a sixth embodiment, R 5 represents difluoromethoxy. In a seventh embodiment, R 5 represents trifluoromethoxy. In an eighth embodiment, R 5 represents -OR a . In one aspect of that embodiment, R 5 represents methoxy. In a ninth embodiment, R 5 represents Ci- 6 alkylsulphonyl. In one aspect of that embodiment, R 5 represents methylsulphonyl. In a tenth embodiment, R 5 represents optionally substituted Ci-6 alkyl. In one aspect of that embodiment, R 5 represents methyl. In another aspect of that embodiment, R 5 represents ethyl.
  • R 5 represents difluoromethoxy or methoxy.
  • R 6 represents hydrogen, halogen or trifluoromethyl.
  • R 6 represents hydrogen. In a second embodiment, R 6 represents halogen. In one aspect of that embodiment, R 6 represents fluoro. In another aspect of that embodiment, R 6 represents chloro. In a third embodiment, R 6 represents trifluoromethyl. In a fourth embodiment, R 6 represents Ci- 6 alkyl. In one aspect of that embodiment, R 6 represents methyl. In another aspect of that embodiment, R 6 represents ethyl. In a fifth embodiment, R 6 represents Ci- 6 alkoxy. In one aspect of that embodiment, R 6 represents methoxy.
  • R 7 represents hydrogen or trifluoromethyl.
  • R 7 represents hydrogen. In a second embodiment, R 7 represents halogen. In one aspect of that embodiment, R 7 represents fluoro. In another aspect of that embodiment, R 7 represents chloro. In a third embodiment, R 7 represents trifluoromethyl. In a fourth embodiment, R 7 represents Ci- 6 alkyl. In one aspect of that embodiment, R 7 represents methyl. In another aspect of that embodiment, R 7 represents ethyl. In a fifth embodiment, R 7 represents Ci- 6 alkoxy. In one aspect of that embodiment, R 7 represents methoxy.
  • R 8 represents hydrogen or trifluoromethyl.
  • R represents hydrogen. In a second embodiment, R represents halogen. In one aspect of that embodiment, R 8 represents fluoro. In another aspect of that embodiment, R 8 represents chloro. In a third embodiment, R 8 represents trifluoromethyl. In a fourth embodiment, R 8 represents Ci- 6 alkyl. In one aspect of that embodiment, R 8 represents methyl. In another aspect of that embodiment, R 8 represents ethyl. In a fifth embodiment, R 8 represents Ci- 6 alkoxy. In one aspect of that
  • R 8 represents methoxy
  • R 12 represents hydrogen or methyl.
  • R 12 represents hydrogen. In a second embodiment, R 12 represents Ci- 6 alkyl. In one aspect of that embodiment, R 12 represents methyl. In another aspect of that embodiment, R 12 represents ethyl.
  • Suitable substituents which may be present on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c , include halogen, Ci- 6 alkyl, Ci- 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci- 6 alkoxy(Ci-6)alkyl, Ci- 6 alkylthio, Ci- 6 alkyl- sulphinyl, Ci- 6 alkylsulphonyl, hydroxy, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano, trifluoromethyl, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkylcarbonyl- oxy, amino, Ci- 6 alkylamino, di(Ci-6)alkylamino, phenylamino, pyridinylamino, C2-6
  • Typical examples of specific substituents which may be present on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxy- carbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamin
  • R a represents Ci- 6 alkyl, aryl(Ci- 6 )alkyl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected examples of suitable substituents on R a include Ci- 6 alkoxy and oxo. - -
  • R a Selected examples of specific substituents on R a include methoxy and oxo.
  • R a represents optionally substituted Ci- 6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted Ci- 6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted Ci- 6 alkyl, e.g.
  • R a represents optionally substituted aryl.
  • R a represents unsubstituted aryl, especially phenyl.
  • R a represents monosubstituted aryl, especially methylphenyl.
  • R a represents optionally substituted aryl(Ci- 6 )alkyl, ideally unsubstituted aryl(Ci-6)alkyl, especially benzyl.
  • R a represents optionally substituted heteroaryl.
  • R a represents optionally substituted heteroaryl(Ci-6)alkyl, e.g. dioxoisoindolylpropyl.
  • R a examples include methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl.
  • R b represents hydrogen or trifluoromethyl; or Ci- 6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or Ci- 6 alkyl, aryl(Ci- 6 )alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical values of R b include hydrogen and Ci- 6 alkyl.
  • R b represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl,
  • pyrrolidinylpropyl thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R b Selected examples of suitable substituents on R b include C 1 -6 alkoxy, Ci- 6 alkylthio, Ci-6 alkylsulphinyl, Ci- 6 alkylsulphonyl, hydroxy, cyano, C2-6 alkoxycarbonyl, di- (Ci-6)alkylamino and C2-6 alkoxy carbonylamino.
  • R b Selected examples of specific substituents on R b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.
  • R b include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino - ethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.
  • R b represents hydrogen. In another embodiment, R b represents Ci- 6 alkyl, especially methyl.
  • R c include hydrogen; or Ci- 6 alkyl, C3-7 cycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R c represents hydrogen, Ci- 6 alkyl or C3-7 cycloalkyl.
  • R c include hydrogen; or methyl, eye lo butyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R c Selected examples of suitable substituents on R c include C2-6 alkylcarbonyl and C2-6 alkoxycarbonyl.
  • R c Selected examples of specific substituents on R c include acetyl and tert- butoxycarbonyl.
  • R c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl,
  • R c represents hydrogen or Ci- 6 alkyl.
  • R c is hydrogen.
  • R c represents Ci- 6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents C3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. - -
  • the moiety -NR b R c may suitably represent azetidin-l-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl,
  • homomorpholin-4-yl or homopiperazin-l-yl any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable substituents on the heterocyclic moiety -NR b R c include Ci- 6 alkyl, Ci- 6 alkylsulphonyl, hydroxy, hydroxy(Ci_6)alkyl, amino(Ci_6)alkyl, cyano, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, amino, C2-6 alkylcarbonyl- amino, C2-6 alkylcarbonylamino(Ci-6)alkyl, C2-6 alkoxycarbonylamino, Ci- 6 alkyl- sulphonylamino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR b R c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.
  • R c Specific values of the moiety -NR b R c include azetidin- 1 -yl, hydroxyazetidin- 1 -yl, hydroxymethylazetidin- 1 -yl, (hydroxy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin-l-yl, cyanoazetidin-l-yl, carboxyazetidin-l-yl, amino azetidin- 1-yl,
  • R d represents hydrogen; or C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R d examples include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, eye lo butyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R d Selected examples of suitable substituents on R d include halogen, Ci- 6 alkyl, Ci- 6 alkoxy, oxo, C2-6 alkylcarbonyloxy and di(Ci-6)alkylamino. - -
  • R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
  • R d represents hydrogen. In another embodiment, R d represents optionally substituted Ci- 6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted Ci- 6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, R d ideally represents substituted Ci- 6 alkyl, e.g. substituted methyl or substituted ethyl, including
  • R d represents optionally substituted aryl.
  • R d represents unsubstituted aryl, especially phenyl.
  • R d represents monosubstituted aryl, especially methylphenyl.
  • R d represents disubstituted aryl, e.g. dimethoxyphenyl.
  • R d represents optionally substituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl.
  • R d represents optionally substituted C3-7 cycloalkyl, e.g. cyclopropyl or cyclo butyl.
  • R d represents optionally substituted C3-7 heterocycloalkyl, e.g. thiazolidinyl or oxo- thiazolidinyl.
  • R d selected examples include hydrogen, methyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-bvXy ⁇ , cyclopropyl, cyclo butyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
  • R e represents Ci- 6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
  • R e Selected examples of suitable substituents on R e include Ci- 6 alkyl, especially methyl.
  • R e represents optionally substituted Ci- 6 alkyl, ideally unsubstituted Ci- 6 alkyl, e.g. methyl or propyl, especially methyl.
  • R e represents optionally substituted aryl.
  • R e represents unsubstituted aryl, especially phenyl.
  • R e represents monosubstituted aryl, especially methylphenyl.
  • R e represents optionally substituted heteroaryl.
  • Selected values of R e include methyl, propyl and methylphenyl.
  • R f represents hydrogen or methyl.
  • R represents hydrogen. In a second embodiment, R represents C e alkyl, especially methyl.
  • R g represents hydrogen or methyl.
  • R g represents hydrogen. In a second embodiment, R g represents Ci- 6 alkyl, especially methyl.
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R f and R g are as defined above.
  • W represents N, CH or CF
  • R 9 represents hydroxy(Ci-6)alkyl or amino(Ci-6)alkyl
  • R 10 represents hydrogen or Ci- 6 alkyl
  • R 2 , R 5 , R 6 , R 7 , R 8 , R f and R g are as defined above.
  • W represents N or CH.
  • W represents N or CF.
  • W represents N. In another embodiment, W represents CH. In a further embodiment, W represents CF.
  • R 9 represents hydroxyisopropyl or aminoisopropyl.
  • Typical values of R 9 include 2-hydroxyprop-2-yl and 2-aminoprop-2-yl.
  • R 9 represents hydroxy(Ci_6)alkyl. In a particular aspect of that embodiment, R 9 represents hydroxyisopropyl, especially 2-hydroxyprop-2-yl.
  • R 9 represents amino(Ci-6)alkyl. In a particular aspect of that embodiment, R 9 represents aminoisopropyl, especially 2-aminoprop-2-yl.
  • R 10 represents hydrogen or methyl.
  • R 10 represents hydrogen. In another embodiment, R 10 represents Ci-6 alkyl. In one aspect of that embodiment, R 10 represents methyl.
  • U represents O, S, S(O), S(0) 2 , S(0)(NR b ), N(R 31 ) or C(R 32 )(R 33 );
  • R 31 represents hydrogen, cyano(Ci_6)alkyl, Ci- 6 alkyl, trifluoromethyl, trifluoro- ethyl, Ci-6 alkylsulphonyl, (Ci-6)alkylsulphonyl(Ci_6)alkyl, formyl, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl(Ci-6)alkyl, aminocarbonyl, Ci- 6 alkylaminocarbonyl, di(Ci-6)alkylamino- carbonyl, aminosulphonyl, Ci- 6 alky lamino sulphonyl or di(Ci- 6 )alky lamino sulphonyl;
  • R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(Ci_6)alkyl, Ci- 6 alkylsulphonyl, formyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6
  • R 33 represents hydrogen, halogen, Ci- 6 alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxy(Ci_6)alkyl, Ci- 6 alkoxy, amino or carboxy;
  • R 34 represents hydrogen, halogen, halo(Ci_6)alkyl, hydroxy, Ci- 6 alkoxy, Ci_6 alkylthio, Ci_6 alkylsulphinyl, Ci_6 alkylsulphonyl, amino, Ci_6 alkylamino, di(Ci_6)alkyl- amino, (C 2 -6)alkylcarbonylamino, (C 2 -6)alkylcarbonylamino(Ci-6)alkyl, (Ci-6)alkyl- sulphony lamino or (Ci-6)alkylsulphonylamino(Ci-6)alkyl;
  • R 35 represents hydrogen or Ci_6 alkyl
  • R 36 and R 37 independently represent Ci- 6 alkyl
  • R 36 and R 37 when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl
  • W, R 2 , R 5 , R 6 , R 7 , R 8 , R 10 , R b , R f and R g are as defined above.
  • U represents O, S(0) 2 , N(R 31 ) or C(R 32 )(R 33 ).
  • U represents O, N(R 31 ) or C(R 32 )(R 33 ).
  • U represents O. In a second embodiment, U represents S. In a third embodiment, U represents S(O). In a fourth embodiment, U represents S(0) 2 . - -
  • U represents S(0)(NR b ). In a sixth embodiment, U represents N(R 31 ). In a seventh embodiment, U represents C(R 32 )(R 33 ).
  • Typical values of R 31 include hydrogen, cyanoethyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl, methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolylmethyl, aminocarbonyl, methylaminocarbonyl, dimethylamino carbonyl, aminosulphonyl, methylaminosulphonyl and dimethylamino sulphonyl.
  • R 31 represents hydrogen or Ci- 6 alkyl.
  • Suitable values of R 31 include hydrogen and methyl.
  • R 31 represents hydrogen. In a second embodiment, R 31 represents Ci- 6 alkyl, especially methyl.
  • Typical values of R 32 include hydrogen, fluoro, cyano, hydroxy, hydroxymethyl, methylsulphonyl, formyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, aminosulphonyl, methylsulphoximinyl, (methyl)(N-methyl)sulphoximinyl, methylsulphonylaminocarbonyl, acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl and hydroxyoxadiazolyl.
  • R 32 represents hydrogen, halogen or cyano.
  • Suitable values of R 32 include hydrogen, fluoro and cyano.
  • R 32 represents hydrogen. In a second embodiment, R 32 represents halogen, especially fluoro. In a third embodiment, R 32 represents cyano.
  • R 33 represents hydrogen, halogen, Ci- 6 alkyl, difluoromethyl or trifluoromethyl.
  • Typical values of R 33 include hydrogen, fluoro, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, amino and carboxy.
  • R 33 represents hydrogen, halogen or difluoromethyl.
  • Suitable values of R 33 include hydrogen, fluoro and difluoromethyl.
  • R 33 represents hydrogen. In a second embodiment, R 33 represents halogen. In one aspect of that embodiment, R 33 represents fluoro. In a third embodiment, R 33 represents Ci- 6 alkyl. In a first aspect of that embodiment, R 33 represents methyl. In a second aspect of that embodiment, R 33 represents ethyl. In a third aspect of that embodiment, R 33 represents isopropyl. In a fourth embodiment, R 33 represents - -
  • R represents difluoromethyl.
  • R represents trifluoromethyl.
  • R 33 represents hydroxy.
  • R 33 represents
  • R 33 represents hydroxy(Ci-6)alkyl. In one aspect of that embodiment, R 33 represents hydroxymethyl. In an eighth embodiment, R 33 represents Ci- 6 alkoxy. In one aspect of that embodiment, R 33 represents methoxy. In a ninth embodiment, R 33 represents amino. In a tenth
  • R 33 represents carboxy
  • R 34 represents hydrogen. In a second embodiment, R 34 represents halogen. In one aspect of that embodiment, R 34 represents fluoro. In a third embodiment, R 34 represents halo(Ci-6)alkyl. In one aspect of that embodiment, R 34 represents fluoromethyl. In a fourth embodiment, R 34 represents hydroxy. In a fifth embodiment, R 34 represents Ci- 6 alkoxy, especially methoxy. In a sixth embodiment, R 34 represents Ci- 6 alkylthio, especially methylthio. In a seventh embodiment, R 34 represents Ci-6 alkylsulphinyl, especially methylsulphinyl. In an eighth embodiment, R 34 represents Ci-6 alkylsulphonyl, especially methylsulphonyl.
  • R 34 represents amino.
  • R 34 represents Ci- 6 alkylamino, especially methylamino.
  • R 34 represents di(Ci-6)alkylamino, especially dimethylamino.
  • R 34 represents (C2-6)alkylcarbonylamino, especially acetylamino.
  • R 34 represents (C2-6)alkylcarbonylamino(Ci-6)alkyl, especially acetylaminomethyl.
  • R 34 represents (Ci_6)alkylsulphonyl- amino, especially methylsulphonylamino.
  • R 34 represents (Ci-6)alkylsulphonylamino(Ci-6)alkyl, especially methylsulphonylaminomethyl.
  • R 34 represents hydrogen or amino
  • Suitable values of R 35 include hydrogen and methyl.
  • R 35 represents hydrogen. In a second embodiment, R 35 represents Ci- 6 alkyl, especially methyl.
  • R 36 represents methyl or ethyl, especially methyl.
  • R 37 represents methyl or ethyl, especially methyl.
  • R 36 and R 37 when taken together with the carbon atom to which they are both attached, may suitably represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders.
  • Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligoarticular and polyarticular forms thereof), anaemia of chronic disease (ACD), Still's disease (juvenile and/or adult onset), Beliefs disease and Sjogren's syndrome.
  • SLE systemic lupus erythematosus
  • psoriasis psoriatic arthropathy
  • Autoimmune endocrine disorders include thyroiditis.
  • Organ-specific autoimmune disorders include Addison's disease, haemo lytic or pernicious anaemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin- induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis
  • osteoporosis osteopenia, erosive bone disease, chondritis, cartilage degeneration and/or destruction, fibrosing disorders (including various forms of hepatic and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatic and axial spondyloarthritis. - -
  • Neurological and neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, ischaemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.
  • Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders
  • Modulators of TNFa function may also be of use in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).
  • Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.
  • Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularisation (including corneal vascularisation and neovascularisation), retinal vein occlusion, and various forms of uveitis (including crizis) and keratitis
  • Oncological disorders which may be acute or chronic, include proliferative disorders, especially cancer, and cancer-associated complications (including skeletal complications, cachexia and anaemia).
  • proliferative disorders especially cancer
  • cancer-associated complications including skeletal complications, cachexia and anaemia.
  • cancer-associated complications including skeletal complications, cachexia and anaemia.
  • haematological malignancy including leukaemia and lymphoma
  • non-haematological malignancy including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma.
  • Chronic leukaemia may be myeloid or lymphoid. Varieties of leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplasia syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia.
  • CML chronic myelogenous leukaemia
  • CLL chronic lymphocytic/lymphoid leukaemia
  • ALL acute lymphoblastic
  • lymphoma Varieties of lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma.
  • Non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, - -
  • Modulators of TNF a function may also be used to increase the safety of the potent anticancer effect of TNF (see F.V. Hauwermeiren et al., J. Clin. Invest., 2013, 123, 2590-2603).
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, micro crystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • wetting agents e.g. sodium lauryl sulphate.
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, - -
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
  • the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a bactericidal or fungicidal agent for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • ophthalmic administration compounds may be formulated in an ointment such as petrolatum.
  • the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but - -
  • Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • a compound in accordance with the present invention may be coadministered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.
  • R p represents C4-9 alkyl; with an acid.
  • Suitable values for the C4-9 alkyl group R p include tert-butyl and 1,1,3,3-tetra- methylbutyl. In a first embodiment, R p represents tert-butyl. In a second embodiment, R p represents 1 , 1 ,3 ,3-tetramethylbutyl.
  • the reaction is suitably effected by treating compound (III) with a mineral acid, e.g. hydrochloric acid, or an organic acid, e.g. trifluoroacetic acid, or a mixture thereof.
  • a mineral acid e.g. hydrochloric acid
  • an organic acid e.g. trifluoroacetic acid, or a mixture thereof.
  • the reaction may be conveniently carried out at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane. - -
  • Q 1 represents chloro or bromo.
  • the transition metal catalyst of use in the above reaction will suitably comprise a mixture of palladium(II) acetate and l, -bis(diphenylphosphino)ferrocene.
  • the reaction will conveniently be effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene.
  • a suitable solvent e.g. a hydrocarbon solvent such as toluene.
  • the reaction will generally be performed in the presence of a base, e.g. an inorganic base such as cesium carbonate.
  • the intermediates of formula (IV) may be prepared from the intermediates of formula (V):
  • A, B, D, Z, E, R 5 , R 12 and Q 1 are as defined above; by a two-step procedure which comprises: (i) reaction with diphenyl phosphoryl azide; and (ii) reaction of the compound thereby obtained with trimethylphosphine.
  • Step (i) of the above procedure is suitably accomplished under basic conditions, e.g. in the presence of an organic base such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • the reaction is conveniently effected at an elevated temperature in a suitable organic solvent, e.g. a hydrocarbon solvent such as toluene.
  • Step (ii) of the above procedure is conveniently effected at ambient temperature in a suitable organic solvent, e.g. a mixture of tetrahydrofuran and toluene, and water.
  • a suitable organic solvent e.g. a mixture of tetrahydrofuran and toluene, and water.
  • the intermediates of formula (V) wherein E represents a group of formula (Ea) as defined above, and R 12 represents hydrogen, may be prepared by a process which comprises the intramolecular cyclization and desilylation of an intermediate of formula (VI):
  • A, B, D, Z, R 1 , R 2 , R 3 , R 4 , R 5 and Q 1 are as defined above.
  • the reaction is suitably performed in the presence of tin(II) chloride at an elevated temperature in a polar solvent, e.g. ethanol.
  • a polar solvent e.g. ethanol.
  • intermediates of formula (VI) as defined above may be prepared by reacting intermediate (VII): - -
  • the intermediate of formula (VII) wherein Q 2 represents -C(0)-H may be prepared from the corresponding compound wherein Q 2 represents -C0 2 R h , in which R h represents C e alkyl, e.g. methyl or ethyl, by reduction with a conventional reducing agent, e.g. a metal hydride such as diisobutylaluminium hydride (DIBAL-H).
  • a conventional reducing agent e.g. a metal hydride such as diisobutylaluminium hydride (DIBAL-H).
  • intermediates of formula (VII) wherein Q 2 represents -C0 2 R h may be obtained by reacting an intermediate of formula (VIII) with an intermediate of formula (IX):
  • the leaving group L 1 is suitably a halogen atom, for example fluorine or bromine.
  • the reaction is conveniently performed in the presence of a base, e.g. an inorganic base such as potassium carbonate, in a suitable solvent, e.g. an apolar solvent such as acetonitrile, at an elevated temperature.
  • a base e.g. an inorganic base such as potassium carbonate
  • a suitable solvent e.g. an apolar solvent such as acetonitrile
  • the intermediates of formula (IX) may be prepared by a multi-step process starting from an intermediate of formula (X): - -
  • A, B, D, R 5 and Q 1 are as defined above; which process comprises the following steps:
  • step (ii) reacting the compound obtained from step (i) with a compound of formula L 2 -Z-Q 2 , wherein Z and Q 2 are as defined above and L 2 is a suitable leaving group, e.g. halogen, such as bromine, and activated zinc metal dust prepared according to conditions described by H. Hilpert et al. in Journal of Medicinal Chemistry, 2013, 56(10), 3980- 3995, typically in the presence of a transition metal salt, e.g. copper(I) chloride, optionally at an elevated temperature; and
  • a transition metal salt e.g. copper(I) chloride
  • the intermediates of formula (X) wherein R 5 represents halogen, e.g. chloro may be transformed into the corresponding intermediate of formula (X) wherein R 5 represents difluoromethoxy by a two-step process which comprises: (i) reaction with potassium hydroxide in water at low temperature; and (ii) reaction with diethyl (bromo- difluoromethyl)phosphonate at low temperature.
  • the intermediates of formula (IV) wherein E represents a group of formula (Ea) as defined above, and R 12 represents hydrogen, may be prepared by a process which comprises the reduction, intramolecular cyclization and desulfmation of an intermediate of formula (Via): - -
  • reaction is conveniently performed in the presence of tin(II) chloride, with the addition of a strong acid, e.g. hydrochloric acid, at an elevated temperature in a suitable solvent, e.g. ethanol.
  • a strong acid e.g. hydrochloric acid
  • the transformation may be effected by a procedure involving: (i) reduction using hydrogen gas under pressure, in the presence of zinc bromide and a hydrogenation catalyst, e.g. platinum on charcoal; and (ii) addition of a strong acid, e.g. hydrochloric acid, at an elevated temperature in a suitable solvent, e.g. ethanol.
  • a hydrogenation catalyst e.g. platinum on charcoal
  • a strong acid e.g. hydrochloric acid
  • the intermediates of formula (Via) may be prepared by a multi-step process starting from an intermediate of formula (Vila):
  • the intermediates of formula (Vila) as defined above may be prepared by reacting an intermediate of formula (VIII) as defined above with an intermediate of formula (IXa):
  • the intermediates of formula (IXa) may be prepared from the intermediates of formula (X) by a process analogous to that described above for the preparation of the intermediates of formula (IX).
  • A, B, D, Z, E, R 5 and Q 1 are as defined above; by reduction of the carbonyl moiety according to methods known to the person skilled in the art.
  • the intermediates of formula (IV) wherein E represents a group of formula (Eb) or (Ec) as defined above, and R 12 represents hydrogen may be prepared from an intermediate of formula (XI) by reaction with a Ci- 6 alkylsulfmamide, e.g. (R)-2- methylpropane-2-sulfinamide, in the presence of a transition metal catalyst, e.g.
  • titanium(IV) ethoxide in a suitable solvent, e.g. dichloromethane; followed by reduction with a suitable reducing agent, e.g. sodium borohydride, in a suitable solvent, e.g.
  • the intermediates of formula (XI) may be prepared by the intramolecular cyclization of an intermediate of formula (XII):
  • V is N or C-R 2
  • Q 4 is an electron-withdrawing group, preferably an ester moiety
  • A, B, D, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R h and Q 1 are as defined above; in the presence of a base.
  • the reaction may conveniently be effected in a suitable solvent at an elevated temperature.
  • the intermediates of formula (XII) may be prepared by reacting an intermediate of formula (XIII) with an intermediate of formula (XIV):
  • the leaving group L 3 is typically a halogen atom, e.g. bromo.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a C 1-4 alkanol such as ethanol, or an ether such as 1,4-dioxane or 1,2- dimethoxyethane, typically in the presence of magnesium sulphate.
  • a suitable solvent e.g. a C 1-4 alkanol such as ethanol, or an ether such as 1,4-dioxane or 1,2- dimethoxyethane, typically in the presence of magnesium sulphate.
  • the intermediates of formula (XII) wherein Z is methylene and Q 4 is -CO2H may be prepared by reacting an intermediate of formula (X) as defined above with an intermediate of formula (XV):
  • V, R 1 , R 3 , R 4 and R h are as defined above; in the presence of Meldrum's acid, according to a method analogous to that described in WO 2009/156091; or by M. Kerr et al. in J. Org. Chem., 2013, 78, 10534.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, in the presence of proline and magnesium sulphate.
  • a suitable solvent e.g. acetonitrile
  • the compounds of formula (I) above, wherein R f represents hydrogen and R g is other than hydrogen may be prepared by a process which comprises reacting a compound of formula R g -NH 2 with a compound of formula (XVI):
  • reaction is conveniently performed at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran.
  • A, B, D, Z, E, R 5 and R 12 are as defined above; with 2,4-bis(4-methoxyphenyl)- l,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent).
  • reaction is conveniently effected at an elevated temperature in a suitable organic solvent, e.g. a hydrocarbon solvent such as toluene.
  • a suitable organic solvent e.g. a hydrocarbon solvent such as toluene.
  • the intermediates of formula (XVII) above may be prepared by the intramolecular cyclisation of a compound of formula (IV) as defined above in the presence of carbon monoxide and a transition metal catalyst.
  • the cyclization is generally effected at an elevated temperature under an elevated pressure of carbon monoxide.
  • the reaction is conveniently carried out in a suitable solvent, e.g. 1,4-dioxane, dimethyl sulfoxide or N,N-dimethylacetamide.
  • the cyclization will generally be performed in the presence of a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate, and/or by activation using molecular sieves.
  • a base e.g. an inorganic base such as sodium carbonate or potassium carbonate
  • molecular sieves e.g. an inorganic base such as sodium carbonate or potassium carbonate
  • the transition metal catalyst of use in the above reaction is suitably selected from dichloro[ 1 ,3-bis(dicyclohexylphosphino)propane]palladium(II), dichloro[9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene]palladium(II) and 2,2-dichloro-l,l,3,3-tetra- cyclohexyl-l 5 ,3 5 -palladocyclohexane.
  • a solution of palladium(II) acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) in a suitable solvent may be used.
  • reaction may be performed using molybdenum hexacarbonyl as an alternative source of carbon monoxide.
  • a compound which contains a hydroxy group may be alkylated by treatment with the appropriate alkyl halide in the presence of a base, e.g. sodium hydride, or silver oxide.
  • a base e.g. sodium hydride, or silver oxide.
  • a compound which contains hydroxy may be converted into the corresponding fluoro-substituted compound by treatment with diethylaminosulfur trifluoride (DAST) or - -
  • BAST bis(2-methoxyethyl)amino sulfur trifluoride
  • a compound which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl halide, typically at an elevated temperature in an organic solvent such as acetonitrile; or at ambient temperature in the presence of a base, e.g. potassium hydroxide, in a suitable solvent, e.g. tetrahydrofuran, in the presence of tetrabutyl- ammonium bromide; or at an elevated temperature in the presence of a base, e.g. sodium hydride, with or without tetrabutylammonium iodate, in a suitable solvent, e.g.
  • tetrahydrofuran or at elevated temperature in the presence of an alkali metal carbonate such as potassium carbonate or cesium carbonate, in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.
  • a suitable solvent e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.
  • a compound which contains an N-H moiety may be methylated by treatment with formaldehyde in the presence of a reducing agent, e.g. sodium triacetoxyborohydride.
  • a compound which contains an N-H moiety may be acylated by treatment with the appropriate acid chloride, e.g. acetyl chloride, or with the appropriate carboxylic acid anhydride, e.g. acetic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine.
  • the appropriate acid chloride e.g. acetyl chloride
  • the appropriate carboxylic acid anhydride e.g. acetic anhydride
  • typically at ambient temperature in the presence of a base e.g. an organic base such as triethylamine.
  • a compound which contains an N-H moiety may be converted into the
  • a compound which contains an N-H moiety may be converted into the
  • a compound substituted by amino (-NH2) may be converted into the corresponding compound substituted by Ci- 6 alkylsulphonylamino, e.g. methylsulphonylamino, or - -
  • Ci- 6 alkylsulphonyl halide e.g. a Ci- 6 alkylsulphonyl chloride such as methanesulphonyl chloride
  • a suitable base e.g. N,N-diisopropylethyl- amine
  • a suitable solvent e.g. dichloromethane
  • a compound substituted by hydroxy may be converted into the corresponding compound substituted by Ci- 6 alkylsulphonyloxy, e.g. methylsulphonyloxy, by treatment with the appropriate Ci- 6 alkylsulphonyl halide, e.g. a Ci- 6 alkylsulphonyl chloride such as methanesulphonyl chloride.
  • Ci- 6 alkylsulphonyloxy e.g. methylsulphonyloxy
  • the appropriate Ci- 6 alkylsulphonyl halide e.g. a Ci- 6 alkylsulphonyl chloride such as methanesulphonyl chloride.
  • a compound containing the moiety -S- may be converted into the corresponding compound containing the moiety -S(O)- by treatment with 3-chloroperoxybenzoic acid.
  • a compound containing the moiety -S(O)- may be converted into the
  • a compound of formula (I) containing the moiety -S- may be converted into the corresponding compound containing the moiety -S(0) 2 - by treatment with Oxone® (potassium peroxymonosulfate).
  • a compound containing an aromatic nitrogen atom may be converted into the corresponding N-oxide derivative by treatment with 3-chloroperoxybenzoic acid.
  • a suitable borohydride reagent e.g. lithium tri-sec-butyl borohydride or sodium borohydride
  • a compound wherein R 1 represents halogen, e.g. chloro or bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted aryl or heteroaryl moiety by treatment with the appropriately substituted aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol.
  • the reaction is typically effected at an elevated temperature in the presence of a transition metal catalyst, e.g.
  • phosphonium tetrafluoroborate or (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, - biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride (XPhos Pd Gl), and a base, e.g. an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate, or potassium phosphate, in a suitable organic solvent, e.g. 1,4-dioxane or n-butanol, and optionally water.
  • a base e.g. an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate, or potassium phosphate
  • a suitable organic solvent e.g. 1,4-dioxane or n-butanol, and optionally water.
  • a compound wherein R 1 represents 2-oxo-(lH)-pyridinyl may be obtained by treatment of the corresponding compound wherein R 1 represents 2-methoxypyridinyl with pyridine hydrochloride at an elevated temperature.
  • a compound wherein R 1 represents an ester moiety may be obtained by reacting the corresponding compound wherein R 1 is halogen, e.g. chloro, with a base, e.g. sodium carbonate, and the appropriate alcohol in the presence of carbon monoxide and a transition metal catalyst, typically [l,3-bis(dicyclohexylphosphino)propane]palladium(II).
  • a transition metal catalyst typically [l,3-bis(dicyclohexylphosphino)propane]palladium(II).
  • a compound wherein R 1 represents cyano may be obtained by reacting the corresponding compound wherein R 1 is halogen, e.g. chloro, with zinc cyanide in the presence of a transition metal catalyst, e.g. tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, e.g. N,N-dimethylformamide.
  • a transition metal catalyst e.g. tetrakis(triphenylphosphine)palladium(0)
  • a hydrogenation catalyst e.g. palladium on charcoal
  • a base e.g. an alkali metal hydroxide such as sodium hydroxide.
  • a compound containing an ester moiety e.g. a C2-6 alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may be converted into the corresponding compound containing a carboxy (-CO2H) moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.
  • an acid e.g. a mineral acid such as hydrochloric acid.
  • a compound containing an ester moiety e.g. a C2-6 alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may alternatively be converted into the
  • a base e.g. an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide and potassium hydroxide; or an organic base such as sodium methoxide or sodium ethoxide.
  • a compound containing a carboxy (-CO2H) moiety may be converted into the corresponding compound containing an amide moiety by treatment with the appropriate - -
  • a condensing agent such as l-ethyl-3-(3-dimethylaminopropyl)- carbodiimide.
  • a compound containing an N-(tert-butoxycarbonyl) moiety may be converted into the corresponding compound containing an N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • a compound containing a hydroxymethyl moiety may be converted into the corresponding compound containing a formyl (-CHO) moiety by treatment with an oxidising agent such as Dess-Martin periodinane.
  • an oxidising agent such as Dess-Martin periodinane.
  • hydroxymethyl moiety may be converted into the corresponding compound containing a carboxy moiety by treatment with an oxidising agent such as tetrapropylammonium perruthenate.
  • a compound containing an aryl or heteroaryl moiety may be transformed into the corresponding compound, wherein a hydrogen atom in the aryl or heteroaryl moiety has been replaced by chloro or bromo, by reaction with N-chlorosuccinimide or N-bromo- succinimide respectively in a suitable solvent, e.g. N,N-dimethylformamide, according to methods known to the person skilled in the art.
  • a suitable solvent e.g. N,N-dimethylformamide
  • a compound containing an aryl moiety bearing a difluoromethoxy group may be transformed into the corresponding compound, wherein the difluoromethoxy group in the aryl moiety has been replaced by a hydroxy group, by reaction with sodium bis(trimethyl- silyl)amide (NaHMDS) in a suitable solvent, e.g. tetrahydrofuran.
  • NaHMDS sodium bis(trimethyl- silyl)amide
  • a compound containing an aryl or heteroaryl moiety may be transformed into the corresponding compound, wherein a hydrogen atom in the aryl or heteroaryl moiety has been replaced by trifluoromethyl, by a stepwise procedure which comprises: (i) treatment with trifluoroacetic acid in a suitable solvent, e.g.
  • a compound substituted by phosphate(Ci_6)alkyl may be prepared from the corresponding compound substituted by hydroxy(Ci_6)alkyl by a stepwise procedure which comprises: (i) treatment with dibenzyl N,N-diisopropylphosphoramidite in a suitable solvent, e.g. dichloromethane, followed by treatment with hydrogen peroxide; and (ii) hydrogeno lysis, e.g. using hydrogen gas under pressure, in the presence of a suitable catalyst, e.g. palladium on charcoal, according to a method analogous to those described by S. P. Green et al. in Organic Process Research & Development, 2002, 6, 109-1 12.
  • a compound substituted by a salt of phosphate(Ci_6)alkyl may be prepared by performing step (ii) in the presence of a suitable alkali metal base or alkaline earth metal base.
  • an isolated compound substituted by phosphate(Ci_6)alkyl may be converted into the corresponding compound substituted by a salt of phosphate(Ci_6)alkyl by treatment with an appropriate base, e.g. an alkali metal base, or an alkaline earth metal base, or ammonia, or an organic amine, in a suitable solvent according to methods known to the person skilled in the art.
  • an appropriate base e.g. an alkali metal base, or an alkaline earth metal base, or ammonia, or an organic amine
  • Suitable alkali metal bases include sodium hydroxide and potassium hydroxide.
  • Suitable alkaline earth metal bases include calcium hydroxide.
  • Suitable organic amines include triethylamine.
  • a compound substituted by (Ci-6)alkylphosphate(Ci_6)alkyl may be prepared from the corresponding compound substituted by hydroxy(Ci_6)alkyl by a stepwise procedure which comprises: (i) reacting cyanoethyl phosphoramidite with the appropriate Ci- 6 alkanol in the presence of a base, e.g. N,N-diisopropylethylamine, in a suitable solvent, e.g. dichloromethane; (ii) addition of the relevant compound substituted by hydroxy- (Ci-6)alkyl in a suitable solvent, e.g.
  • a compound substituted by sulphate(Ci_6)alkyl may be prepared by treatment of the corresponding compound substituted by hydroxy(Ci_6)alkyl with pyridine: sulphur trioxide complex, according to a method analogous to that described by E. Lacko et al. in Current Medicinal Chemistry, 2012, 19, 4699; or by treatment with chlorosulphonic acid in the presence of triethylamine, according to a method analogous to that described in WO 2004/087720. - -
  • a compound substituted by phosphate-methoxy(Ci-6)alkyl may be prepared by reacting the corresponding compound substituted by hydroxy(Ci-6)alkyl with a suitable base, e.g. sodium hydride, in a suitable solvent, e.g. 1 ,2-dimethoxyethane, followed by addition of chloromethyl di-tert-butylphosphate, with subsequent dealkylation at an elevated temperature, according to a method analogous to that described in
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
  • HEK-293 derived reporter cell line known as HEK-BlueTM CD40L.
  • SEAP secreted embryonic alkaline phosphatase
  • compounds of the present invention When tested in the HEK-293 bioassay, also referred to herein as the reporter gene assay, compounds of the present invention exhibit an IC50 value of 50 ⁇ or less, generally of 20 ⁇ or less, usually of 5 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 25 nM or less (the skilled person will appreciate that a lower IC50 figure denotes a more active compound).
  • Certain compounds in accordance with the present invention potently inhibit the binding of a fluorescence conjugate to TNFa when tested in the fluorescence polarisation assay described herein. Indeed, when tested in that assay, compounds of the present invention exhibit an IC50 value of 50 ⁇ or less, generally of 20 ⁇ or less, usually of 5 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 25 nM or less (as before, the skilled person will appreciate that a lower IC50 figure denotes a more active compound).
  • Carboxy- fluorescein succinimyl ester (24.16 mg, 0.0510 mmol) (Invitrogen catalogue number: C1311) was dissolved in DMSO (1 mL) to give a bright yellow solution. The two solutions were mixed at room temperature, the mixture turning red in colour. The mixture was stirred at room temperature. Shortly after mixing a 20 aliquot was removed and diluted in a 80:20 mixture of AcOH:H 2 0 for LC-MS analysis on the
  • the mixture was purified on a UV-directed preparative HPLC system.
  • the pooled purified fractions were freeze-dried to remove excess solvent. After freeze-drying, an orange solid (23.3 mg) was recovered, equivalent to 0.027 mmol of fluorescence conjugate, corresponding to an overall yield of 53% for the reaction and preparative HPLC purification.
  • IC50 value was calculated using XLfitTM (4 parameter logistic model) in ActivityBase.
  • IC50 values generally in the range of about 0.01 nM to about 50 ⁇ , usually in the range of about 0.01 nM to about 20 ⁇ , typically in the range of about 0.01 nM to about 5 ⁇ , suitably in the range of about 0.01 nM to about 1 ⁇ , ideally in the range of about 0.01 nM to about 500 nM, appositely in the range of about 0.01 nM to about 100 nM, and preferably in the range of about 0.01 nM to about 25 nM.
  • Stimulation of HEK-293 cells by TNFa leads to activation of the NF- ⁇ pathway.
  • HEK-BlueTM CD40L is a stable HEK-293 transfected cell line expressing SEAP (secreted embryonic alkaline phosphatase) under the control of the IFNP minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a dose- dependent manner by TNFa, with an EC50 of 0.5 ng/mL for human TNFa.
  • Compounds were diluted from 10 mM DMSO stocks (final assay concentration 0.3% DMSO) to generate a 10-point 3-fold serial dilution curve (e.g. 30,000 nM to 2 nM final
  • Detection media (InvivoGen). Percentage inhibitions for compound dilutions were calculated between a DMSO control and maximum inhibition (by excess control compound) and an IC50 value calculated using XLfitTM (4 parameter logistic model) in ActivityBase.
  • compounds of the accompanying Examples exhibit IC50 values generally in the range of about 0.01 nM to about 50 ⁇ , usually in the range of about 0.01 nM to about 20 ⁇ , typically in the range of about 0.01 nM to about 5 ⁇ , suitably in the range of about 0.01 nM to about 1 ⁇ , appositely in the range of about 0.01 nM to about 500 nM, ideally in the range of about 0.01 nM to about 100 nM, and preferably in the range of about 0.01 nM to about 25 nM.
  • DIBAL-H diisobutylaluminium hydride
  • TFA trifluoroacetic acid
  • DIAD diisopropyl (E)-l,2-diazenedicarboxylate
  • Lawesson' s reagent 2,4-bis(4-methoxyphenyl)- 1 ,3 ,2,4-dithiadiphosphetane-2,4-dithione
  • XPhos Pd Gl (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) chloride
  • a QDA Waters simple quadrupole mass spectrometer is used for LC-MS analysis.
  • This spectrometer is equipped with an ESI source and an UPLC Acquity Classic with diode array detector (210 to 400 nm).
  • Data are acquired in a full MS scan from mlz 50 to 1000 in positive mode with an acidic elution.
  • the reverse phase separation is carried out at 45 °C on a Waters Acquity UPLC BEH C18 1.7 ⁇ (2.1 x 50 mm) column for basic elution.
  • a QDA Waters simple quadrupole mass spectrometer is used for LC-MS analysis. This spectrometer is equipped with an ESI source and an UPLC Acquity Hclass with diode array detector (210 to 400 nm).
  • Data are acquired in a full MS scan from mlz 50 to 1000 in positive mode with an acidic elution.
  • the reverse phase separation is carried out at 45 °C on a Waters Acquity UPLC HSS T3 1.8 ⁇ (2.1 x 50 mm) column for acidic elution.
  • pH3_35_50 focused gradient, reverse phase.
  • Solvent B acetonitrile + 0.1% formic acid
  • pH10_35_30 focused gradient, reverse phase.
  • Solvent A 10 mM ammonium bicarbonate + 0.1% ⁇ 4 ⁇
  • Zinc powder (150 g) was taken up in IN HC1 (500 mL), stirred for 10 minutes and decanted. The zinc dust powder was washed with water (3 x 500 mL) and decanted. The powder was further washed with acetone (3 x 500 mL), decanted and dried under vacuum. To the resulting activated zinc dust (105 g, 1618 mmol) in dry THF (150 mL) was added CuCl (19.2 g, 194 mmol) and the reaction mixture was heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature and ethyl bromo- acetate (45 mL, 404 mmol) in THF (100 mL) was added dropwise. The reaction mixture - -
  • the aqueous phase was extracted three times with EtOAc, then the organic phases were combined and washed sequentially with aqueous ammonium chloride solution and saturated aqueous sodium hydrogen carbonate solution.
  • the organic phase was separated and dried (MgS0 4 ), then filtered and concentrated in vacuo. The crude residue was - -

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une série de dérivés d'imidazole pentacycliques condensés substitués qui sont de puissants modulateurs de l'activité du TNFα humain, et sont ainsi efficaces dans le traitement et/ou la prévention de diverses affections humaines, dont les troubles auto-immuns et inflammatoires ; les troubles neurologiques et neurodégénératifs ; la douleur et les troubles nociceptifs ; les troubles cardiovasculaires ; les troubles métaboliques ; les troubles oculaires ; et les troubles oncologiques.
EP17714785.7A 2016-04-01 2017-03-31 Dérivés d'imidazole pentacyclique condensé comme modulateurs de l'activité du tnf Active EP3436460B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16163579 2016-04-01
PCT/EP2017/057767 WO2017167994A1 (fr) 2016-04-01 2017-03-31 Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf

Publications (2)

Publication Number Publication Date
EP3436460A1 true EP3436460A1 (fr) 2019-02-06
EP3436460B1 EP3436460B1 (fr) 2021-08-18

Family

ID=55650327

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17714785.7A Active EP3436460B1 (fr) 2016-04-01 2017-03-31 Dérivés d'imidazole pentacyclique condensé comme modulateurs de l'activité du tnf

Country Status (8)

Country Link
US (1) US10654861B2 (fr)
EP (1) EP3436460B1 (fr)
JP (1) JP6968090B2 (fr)
CN (1) CN109195968B (fr)
BR (1) BR112018069941A2 (fr)
CA (1) CA3019245A1 (fr)
EA (1) EA201892142A1 (fr)
WO (1) WO2017167994A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201510758D0 (en) 2015-06-18 2015-08-05 Ucb Biopharma Sprl Novel TNFa structure for use in therapy
GB201621907D0 (en) 2016-12-21 2017-02-01 Ucb Biopharma Sprl And Sanofi Antibody epitope
WO2020084008A1 (fr) * 2018-10-24 2020-04-30 UCB Biopharma SRL Dérivés d'imidazole pentacycliques fusionnés utilisés en tant que modulateurs de l'activité du tnf

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0408477A (pt) 2003-03-10 2006-04-04 Pfizer compostos de éster de fosfato/sulfato e composições farmacêuticas para inibir a nima de interação com proteìna (pin 1) e uso dos mesmos
TW200615273A (en) * 2004-11-10 2006-05-16 Nicholas Piramal India Ltd Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
DE102008030206A1 (de) 2008-06-25 2009-12-31 Bayer Schering Pharma Aktiengesellschaft 3-Cyanoalky- und 3-Hydroxyalkyl-Indole und ihre Verwendung
TW201242953A (en) 2011-03-25 2012-11-01 Bristol Myers Squibb Co Imidazole prodrug LXR modulators
TWI554515B (zh) 2011-06-20 2016-10-21 維泰克斯製藥公司 旋轉酶（ｇｙｒａｓｅ）及拓樸異構酶抑制劑之磷酸酯
US9550737B2 (en) 2012-06-11 2017-01-24 Ucb Biopharma Sprl TNF -α modulating benzimidazoles
GB201212513D0 (en) 2012-07-13 2012-08-29 Ucb Pharma Sa Therapeutic agents
WO2014009295A1 (fr) 2012-07-13 2014-01-16 Ucb Pharma S.A. Dérivés d'imidazopyridine utilisables en tant que modulateurs de l'activité tnf
GB201321729D0 (en) * 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321728D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321730D0 (en) * 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
MA40770B1 (fr) 2014-10-03 2021-11-30 Sanofi Sa Dérivés d'imidazoles pentacyclic fusionnés

Also Published As

Publication number Publication date
CA3019245A1 (fr) 2017-10-05
WO2017167994A1 (fr) 2017-10-05
US20190100525A1 (en) 2019-04-04
EA201892142A1 (ru) 2019-04-30
CN109195968B (zh) 2022-02-11
US10654861B2 (en) 2020-05-19
BR112018069941A2 (pt) 2019-02-05
JP6968090B2 (ja) 2021-11-17
EP3436460B1 (fr) 2021-08-18
JP2019512533A (ja) 2019-05-16
CN109195968A (zh) 2019-01-11

Similar Documents

Publication Publication Date Title
US9890154B2 (en) Imidazopyridine derivatives as modulators of TNF activity
EP3080126A1 (fr) Dérivés de purine à titre de modulateurs de l'activité du tnf
EP3436459B1 (fr) Dérivés d'imidazole pentacyclique fusionnés comme modulateurs de l'activité de la tnf
WO2015086511A1 (fr) Dérivés de triazolopyridazine à titre de modulateurs de l'activité du tnf
US9834553B2 (en) Tetrahydroimidazopyridine derivatives as modulators of TNF activity
WO2016198398A1 (fr) Imidazopyrazines tricycliques condensées à titre de modulateurs de l'activité du tnf
US10654861B2 (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
US10766906B2 (en) Fused hexacyclic imidazole derivatives as modulators of TNF activity
US10793578B2 (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
JP7121033B2 (ja) Ｔｎｆ活性のモジュレーターとしての縮合五環式イミダゾール誘導体

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20181029

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI

Owner name: UCB BIOPHARMA SRL

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20200713

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602017044237

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: C07D0487040000

Ipc: A61K0031418800

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 31/00 20060101AFI20210223BHEP

Ipc: C07D 487/18 20060101ALI20210223BHEP

Ipc: A61P 3/00 20060101ALI20210223BHEP

Ipc: A61P 37/02 20060101ALI20210223BHEP

Ipc: A61P 9/00 20060101ALI20210223BHEP

Ipc: A61P 25/04 20060101ALI20210223BHEP

Ipc: A61P 25/00 20060101ALI20210223BHEP

Ipc: A61P 27/02 20060101ALI20210223BHEP

Ipc: C07D 487/04 20060101ALI20210223BHEP

Ipc: A61P 43/00 20060101ALI20210223BHEP

Ipc: A61P 29/00 20060101ALI20210223BHEP

Ipc: A61P 35/00 20060101ALI20210223BHEP

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/4188 20060101AFI20210303BHEP

Ipc: A61P 35/00 20060101ALI20210303BHEP

Ipc: C07D 487/18 20060101ALI20210303BHEP

Ipc: A61P 27/02 20060101ALI20210303BHEP

Ipc: A61P 43/00 20060101ALI20210303BHEP

Ipc: C07D 487/04 20060101ALI20210303BHEP

Ipc: A61P 25/00 20060101ALI20210303BHEP

Ipc: A61P 29/00 20060101ALI20210303BHEP

Ipc: A61P 9/00 20060101ALI20210303BHEP

Ipc: A61P 25/04 20060101ALI20210303BHEP

Ipc: A61P 37/02 20060101ALI20210303BHEP

INTG Intention to grant announced

Effective date: 20210319

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602017044237

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Ref country code: AT

Ref legal event code: REF

Ref document number: 1420994

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210915

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20210818

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1420994

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210818

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20211118

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20211118

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20211220

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20211119

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602017044237

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20220519

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20220331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220331

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220331

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220331

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220331

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230208

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20170331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210818

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240206

Year of fee payment: 8

Ref country code: GB

Payment date: 20240108

Year of fee payment: 8